Biology Reference
In-Depth Information
Other highly active immunogenic components of Gram-positive bacteria
are the exotoxins, which act mainly as antigens that activate T cells,
leading to the generation of high levels of IL-8 and low levels of TNFα,
IL-1, and IL-6. A more thorough comparison between the two responses
has been described (Amersfoort
et al.
, 2003).
6.1.4
Small molecule mediators of LPS/TNF
α
-induced septic shock
response
Several small molecules belonging to diverse structural classes either
enhance or inhibit the native immunostimulatory response to LPS.
Although the exact molecular target has not been discovered for many of
these compounds, for some species this point is settled. These small
molecule mediators act through several distinct targets within the
recognition, signaling pathway, transcription, translation, and post-
translational protein modification systems.
Besides small molecule modulators, several biological mediators
such as growth hormone, catecholamines, and IL-10 also have been
studied. Some peptide-based drug candidates are currently in clinical
studies as cytokine inhibitors for the treatment of various inflammatory
diseases. These agents include the soluble p75 TNFα receptor Etanercept
(Enbrel), the human TNFα antibodies Infliximab (Remicade),
Adalimumab (Humira), and Golimumab (CNTO 148), and the human
IL-1 receptor antagonist Anakinra. Today, all of the approved anti-
cytokine drugs are peptide-based, although some small molecules are
currently in clinical trials.
6.1.4.1
LPS agonists
There are very few reports of LPS (lipid A) agonists in the literature.
One example is the microtubule stabilizer taxol (
7
, Fig. 6.5), which
mimics LPS in decreasing TNFR cell surface expression and promoting
TNFα release (Ding
et al.
, 1990, Byrd-Leifer
et al.
, 2001). It has been
reported to act by binding to TLR4. In addition, some 4-
O
-phosphono-
D
-
glucosamine derivatives such as GLA-60 (
8
) and its analogues have
shown agonistic properties. Synthetic acyclic lipid A-like analogues such
